The dominant existing methods for high-throughput drug discovery currently involve fluorescent or radioactive labeling of a target molecule. This is disadvantageous in that a new assay must be designed for each target molecule, a costly and time-consuming process. Moreover, the label may interfere with the natural biological activity of the target molecule. Current techniques are discussed by Macarrón et al., “Design and implementation of high-throughput screening assays,” in Janzen, ed., High Throughput Screening: Methods and Protocols, (2002), which is incorporated herein by reference.
Thermodynamic indicators of reaction progress in microsamples would obviate the development of specific labels, however existing microcalorimeters lack the resolution and/or throughput (i.e., adaptability to parallel measurement) needed for high throughput drug discovery.
Several types of thermometers with microkelvin-level resolution at room temperature have been reported in the literature. Smith et al., Quartz crystal thermometer for measuring temperature deviations in the 10−3 to 10−6° C. range, Rev. Sci. Instrum., vol. 34, pp. 268-70 (1963) describe a quartz resonator with a measured noise level of 4 μK. A thermistor with sub-microkelvin noise is mentioned in Hansen et al., Comparison of the detection limits of microcalorimeters, Thermochim. Acta, vol. 70 pp. 257-268 (1983). Similar thermostats have been used to measure the properties of liquids near their critical points, as described, for example by Cohen et al., Viscosity of dilute poly-electrolyte solutions, J. Chem. Phys., vol. 88, pp. 7111-16, (1988). Finally, thermopiles may be used to measure small temperature differences such as in the thermopile microcalorimeter described by Velázquez-Campoy et al., Development of an isothermal titration microcalorimetric system with digital control and dynamic power Peltier compensation. I. Description and basic performance, Rev. Sci. Instrum., vol. 71, pp. 1824-31 (2000).
Interferometry has been used to measure the expansion of solids and liquid crystals, such as by Joly et al., Thermodilatometric measurements on small samples of liquid crystals, J. Therm. Anal., vol. 37, pp. 2483-95 (1991), incorporated herein by reference. Instrumental use of interferometry to record meniscus levels has been limited to manometers where such techniques were possible by virtue of the large meniscus cross-section, but were found to be limited in resolution due to vibration problems, as discussed by Tilford, Three and a halfcenturies later—the modern art of liquid-column manometry, Metrologia, vol. 30, 545-52 (1994), incorporated herein by reference.